Inhibitors of serine protease, particularly hcv ns3-ns4a protease

ABSTRACT

The present invention relates to compounds of formula I: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, or mixtures thereof, that inhibit serine protease activity, particularly the activity of hepatitis C virus NS3-NS4A protease. As such, they act by interfering with the life cycle of the hepatitis C virus and are useful as antiviral agents. The invention further relates to pharmaceutically acceptable compositions comprising said compounds either for ex vivo use or for administration to a patient suffering from HCV infection and processes for preparing the compounds. The invention also relates to methods of treating an HCV infection in a patient by administering a pharmaceutical composition comprising a compound of this invention.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of U.S. ProvisionalApplication No. 60/513,765, filed Oct. 23, 2003, entitled “Inhibitors ofSerine Proteases, Particularly HCV NS3-NS4A Protease”, the entirecontents of which is hereby incorporated by reference. The presentapplication also claims the benefit of U.S. patent application Ser. No.10/412,600, filed Apr. 11, 2003, entitled “Inhibitors of SerineProteases, Particularly HCV NS3-NS4A Protease”, the entire contents ofwhich is hereby incorporated by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds that inhibit serine proteaseactivity, particularly the activity of hepatitis C virus NS3-NS4Aprotease. As such, they act by interfering with the life cycle of thehepatitis C virus and are also useful as antiviral agents. The inventionfurther relates to pharmaceutical compositions comprising thesecompounds either for ex vivo use or for administration to a patientsuffering from HCV infection. The invention also relates to processesfor preparing the compounds and methods of treating an HCV infection ina patient by administering a pharmaceutical composition comprising acompound of this invention.

BACKGROUND OF THE INVENTION

Infection by hepatitis C virus (“HCV”) is a compelling human medicalproblem. HCV is recognized as the causative agent for most cases ofnon-A, non-B hepatitis, with an estimated human sero-prevalence of 3%globally [A. Alberti et al., “Natural History of Hepatitis C,” J.Hepatology, 31., (Suppl. 1), pp. 17-24 (1999)]. Nearly four millionindividuals may be infected in the United States alone [M. J. Alter etal., “The Epidemiology of Viral Hepatitis in the United States,Gastroenterol. Clin. North Am., 23, pp. 437-455 (1994); M. J. Alter“Hepatitis C Virus Infection in the United States,” J. Hepatology, 31.,(Suppl. 1), pp. 88-91 (1999)].

Upon first exposure to HCV only about 20% of infected individualsdevelop acute clinical hepatitis while others appear to resolve theinfection spontaneously. In almost 70% of instances, however, the virusestablishes a chronic infection that persists for decades [S. Iwarson,“The Natural Course of Chronic Hepatitis,” FEMS Microbiology Reviews,14, pp. 201-204 (1994); D. Lavanchy, “Global Surveillance and Control ofHepatitis C,” J. Viral Hepatitis, 6, pp. 35-47 (1999)]. This usuallyresults in recurrent and progressively worsening liver inflammation,which often leads to more severe disease states such as cirrhosis andhepatocellular carcinoma [M. C. Kew, “Hepatitis C and HepatocellularCarcinoma”, FEMS Microbiology Reviews, 14, pp. 211-220 (1994); I. Saitoet. al., “Hepatitis C Virus Infection is Associated with the Developmentof Hepatocellular Carcinoma,” Proc. Natl. Acad. Sci. USA, 87, pp.6547-6549 (1990)]. Unfortunately, there are no broadly effectivetreatments for the debilitating progression of chronic HCV.

The HCV genome encodes a polyprotein of 3010-3033 amino acids [Q. L.Choo, et. al., “Genetic Organization and Diversity of the Hepatitis CVirus.” Proc. Natl. Acad. Sci. USA, 88, pp. 2451-2455 (1991); N. Kato etal., “Molecular Cloning of the Human Hepatitis C Virus Genome FromJapanese Patients with Non-A, Non-B Hepatitis,” Proc. Natl. Acad. Sci.USA, 87, pp. 9524-9528 (1990); A. Takamizawa et. al., “Structure andOrganization of the Hepatitis C Virus Genome Isolated From HumanCarriers,” J. Virol., 65, pp. 1105-1113 (1991)]. The HCV nonstructural(NS) proteins are presumed to provide the essential catalytic machineryfor viral replication. The NS proteins are derived by proteolyticcleavage of the polyprotein [R. Bartenschlager et. al., “NonstructuralProtein 3 of the Hepatitis C Virus Encodes a Serine-Type ProteinaseRequired for Cleavage at the NS3/4 and NS4/5 Junctions,” J. Virol., 67,pp. 3835-3844 (1993); A. Grakoui et. al., “Characterization of theHepatitis C Virus-Encoded Serine Proteinase: Determination ofProteinase-Dependent Polyprotein Cleavage Sites,” J. Virol., 67, pp.2832-2843 (1993); A. Grakoui et. al., “Expression and Identification ofHepatitis C Virus Polyprotein Cleavage Products,” J. Virol., 67, pp.1385-1395 (1993); L. Tomei et. al., “NS3 is a serine protease requiredfor processing of hepatitis C virus polyprotein”, J. Virol., 67, pp.4017-4026 (1993)].

The HCV NS protein 3 (NS3) contains a serine protease activity thathelps process the majority of the viral enzymes, and is thus consideredessential for viral replication and infectivity. It is known thatmutations in the yellow fever virus NS3 protease decrease viralinfectivity [Chambers, T. J. et. al., “Evidence that the N-terminalDomain of Nonstructural Protein NS3 From Yellow Fever Virus is a SerineProtease Responsible for Site-Specific Cleavages in the ViralPolyprotein”, Proc. Natl. Acad. Sci. USA, 87, pp. 8898-8902 (1990)]. Thefirst 181 amino acids of NS3 (residues 1027-1207 of the viralpolyprotein) have been shown to contain the serine protease domain ofNS3 that processes all four downstream sites of the HCV polyprotein [C.Lin et al., “Hepatitis C Virus NS3 Serine Proteinase: Trans-CleavageRequirements and Processing Kinetics”, J. Virol., 68, pp. 8147-8157(1994)].

The HCV NS3 serine protease and its associated cofactor, NS4A, helpsprocess all of the viral enzymes, and is thus considered essential forviral replication. This processing appears to be analogous to thatcarried out by the human immunodeficiency virus aspartyl protease, whichis also involved in viral enzyme processing. HIV protease inhibitors,which inhibit viral protein processing, are potent antiviral agents inman, indicating that interrupting this stage of the viral life cycleresults in therapeutically active agents. Consequently HCV NS3 serineprotease is also an attractive target for drug discovery.

Furthermore, the current understanding of HCV has not led to any othersatisfactory anti-HCV agents or treatments. Until recently, the onlyestablished therapy for HCV disease was interferon treatment. However,interferons have significant side effects [M. A. Wlaker et al.,“Hepatitis C Virus: An Overview of Current Approaches and Progress,”DDT, 4, pp. 518-29 (1999); D. Moradpour et al., “Current and EvolvingTherapies for Hepatitis C,” Eur. J. Gastroenterol. Hepatol., 11, pp.1199-1202 (1999); H. L. A. Janssen et al. “Suicide Associated withAlfa-Interferon Therapy for Chronic Viral Hepatitis,” J. Hepatol., 21,pp. 241-243 (1994); P. F. Renault et al., “Side Effects of AlphaInterferon,” Seminars in Liver Disease, 9, pp. 273-277. (1989)] andinduce long term remission in only a fraction (˜25%) of cases [O.Weiland, “Interferon Therapy in Chronic Hepatitis C Virus Infection”,FEMS Microbiol. Rev., 14, pp. 279-288 (1994)]. Recent introductions ofthe pegylated forms of interferon (PEG-Intron® and Pegasys®) and thecombination therapy of ribavirin and pegylated interferon (Rebetrol®)have resulted in only modest improvements in remission rates and onlypartial reductions in side effects. Moreover, the prospects foreffective anti-HCV vaccines remain uncertain.

Thus, there is a need for more effective anti-HCV therapies. Suchinhibitors would have therapeutic potential as protease inhibitors,particularly as serine protease inhibitors, and more particularly as HCVNS3 protease inhibitors. Specifically, such compounds may be useful asantiviral agents, particularly as anti-HCV agents.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula I:

or a pharmaceutically acceptable salt, or mixtures thereof, wherein:

-   W is:

-   -   wherein each R₆ is independently:        -   hydrogen-,        -   (C1-C12)-aliphatic-,        -   (C6-C10)-aryl-,        -   (C6-C10)-aryl-(C1-C12)aliphatic-,        -   (C3-C10)-cycloalkyl- or cycloalkenyl-,        -   [(C3-C10)-cycloalkyl- or cycloalkenyl]-(C1-C12)-aliphatic-,        -   (C3-C10)-heterocyclyl-,        -   (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,        -   (C5-C10)-heteroaryl-, or        -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-, or        -   wherein up to 3 aliphatic carbon atoms in each R₆ may be            optionally replaced with S, —S(O)—, —S(O)₂—, —O—, —N—, or            —N(H)— in a chemically stable arrangement;        -   wherein R₆ may be optionally substituted with up to 3 J            substituents; or        -   two R₆ groups, together with the nitrogen atom to which they            are bound, may optionally form a 5- to 6-membered aromatic            or a 3- to 7-membered saturated or partially unsaturated            ring system wherein up to 3 ring atoms may be optionally            replaced with N, NH, O, S, SO, and SO₂, wherein said ring            system may be optionally fused to a (C6-C10)aryl,            (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a            (C3-C10)heterocyclyl, wherein any ring has up to 3            substituents selected independently from J;        -   wherein each R₈ is independently —OR′; or the R₈ groups            together with the boron atom, may optionally form a            (C3-C10)-membered heterocyclic ring having, in addition to            the boron, up to 3 ring atoms optionally replaced with N,            NH, O, S, SO, and SO₂;

-   J is halogen, —OR′, —NO₂, —CN, —CF₃, —OCF₃, —R′, oxo, thioxo,    ═N(R′), ═N(OR′), 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R′)₂,    —SR′, —SOR′, —SO₂R′, —SO₂N(R′)₂, —SO₃R′, —C(O)R′, —C(O)C(O)R′,    —C(O)C(O)OR′, —C(O)C(O)NR′, —C(O)CH₂C(O)R′, —C(S)R′, —C(S)OR′,    —C(O)OR′, —OC(O)R′, —C(O)N(R′)₂, —OC(O)N(R′)₂, —C(S)N(R′)₂,    —(CH₂)₀₋₂NHC(O)R′, —N(R′)N(R′)COR′, —N(R′)N(R′)C(O)OR′,    —N(R′)N(R′)CON(R′)₂, —N(R′)SO₂R′, —N(R′)SO₂N(R′)₂, —N(R′)C(O)OR′,    —N(R′)C(O)R′, —N(R′)C(S)R′, —N(R′)C(O)N(R′)₂, —N(R′)C(S)N(R′)₂,    —N(COR′)COR′, —N(OR′)R′, —C(═NH)N(R′)₂, —C(O)N(OR′)R′, —C(═NOR′)R′,    —OP(O)(OR′)₂, —P(O)(R′)₂, —P(O)(OR′)₂, or —P(O)(H)(OR′); wherein;    -   R′ is independently selected from:    -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)aliphatic-,    -   (C5-C10)-heteroaryl-, and    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;    -   wherein up to 5 atoms in R′ may be optionally and independently        substituted with J;    -   wherein two R′ groups bound to the same atom may optionally form        a 5- to 6-membered aromatic or a 3- to 7-membered saturated or        partially unsaturated ring system wherein up to 3 ring atoms may        be optionally replaced with a heteroatom independently selected        from N, NH, O, S, SO, and SO₂, wherein said ring system may be        optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl,        (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, wherein any ring        has up to 3 substituents selected independently from J;

-   R₅ and R_(5′) are each independently hydrogen or (C1-C12)-aliphatic,    wherein any hydrogen may be optionally replaced with halogen;    wherein any terminal carbon atom of R₅ may be optionally substituted    with sulfhydryl or hydroxy; or R₅ is Ph or —CH₂Ph and R_(5′) is H,    wherein said Ph or —CH₂Ph group may be optionally substituted with    up to 3 substituents independently selected from J; or

-   R₅ and R_(5′) together with the atom to which they are bound may    optionally form a 3- to 6-membered saturated or partially    unsaturated ring system wherein up to 2 ring atoms may be optionally    replaced with N, NH, O, SO, or SO₂; wherein said ring system has up    to 2 substituents selected independently from J;

-   R₂, R₄, and R₇ are each independently:    -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl-(C1-C12)-aliphatic-, or    -   (C6-C10)-aryl-(C1-C12)-aliphatic-;        -   wherein up to two aliphatic carbon atoms in each of R₂, R₄,            and R₇ may be optionally replaced with S, —S(O)—, —S(O)₂—,            —O—, —N—, or —N(H)— in a chemically stable arrangement;        -   wherein each of R₂, R₄, and R₇ may be independently and            optionally substituted with up to 3 substituents            independently selected from J;

-   R₁ and R₃ are each independently:    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl- or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein up to 3 aliphatic carbon atoms in each of R₁ and R₃            may be optionally replaced with S, —S(O)—, —S(O)₂—, —O—,            —N—, or —N(H)— in a chemically stable arrangement;        -   wherein each of R₁ and R₃ may be independently and            optionally substituted with up to 3 substituents            independently selected from J;

-   R₉, R_(9′), R₁₀, and R_(10′) are each independently —X—Y-Z;

-   X is a bond, —C(H)(R₆)—, —O—, —S—, or —N(R₁₁)—;

-   R₁₁ is:    -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-cycloalkyl- or cycloalkenyl-,    -   [(C3-C10)-cycloalkyl- or cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-,        -   wherein up to 3 aliphatic carbon atoms in each R₁₁ may be            optionally replaced with S, —S(O)—, —S(O)₂—, —O—, —N—, or            —N(H)— in a chemically stable arrangement;        -   wherein R₁₁ may be optionally substituted with up to 3 J            substituents; or        -   wherein R₁₁ and Z together with the atoms to which they are            bound, optionally form a nitrogen containing 5-7-membered            mono- or 6-11-membered bicyclic ring system optionally            substituted with up to 3 J substitutents, wherein up to 3            ring atoms in said ring system may be optionally replaced            with O, NH, S, SO, or SO₂ in a chemically stable            arrangement;

-   Y is a bond, —CH₂—, —C(O)—, —C(O)C(O)—, —S(O)—, S(O)₂—, or    —S(O)(NR₁₂)—;

-   R₁₂ is:    -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-cycloalkyl- or cycloalkenyl-,    -   [(C3-C10)-cycloalkyl- or cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-,        -   wherein up to 3 aliphatic carbon atoms in each R₁₂ may be            optionally replaced with S, —S(O)—, —S(O)₂—, —O—, —N—, or            —N(H)—, in a chemically stable arrangement;        -   wherein R₁₂ may be optionally substituted with up to 3 J            substituents;

-   Z is:    -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-heterocyclyl-,        -   (C3-C10)-heterocyclyl-(C1-C12)aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein up to three aliphatic carbon atoms in Z may be            optionally replaced with S, —S(O)—, —S(O)₂—, —O—, —N—, or            —N(H)—, in a chemically stable arrangement;        -   wherein any ring may be optionally fused to a (C6-C10)aryl,            (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or            (C3-C10)heterocyclyl;        -   wherein Z may be independently and optionally substituted            with up to 3 substituents independently selected from J;

-   V is —C(O)—, —S(O)—, or —S(O)₂—;

-   R is —C(O)—, —S(O)—, —S(O)₂—, —N(R₁₂)—, —O—, or a bond;

-   T is:    -   (C1-C12)-aliphatic-;    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-cycloalkyl or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein up to 3 aliphatic carbon atoms in T may be replaced            with S, —S(O)—, —S(O)₂—, —O—, —N—, or —N(H)—, in a            chemically stable arrangement;        -   wherein each T may be optionally substituted with up to 3 J            substituents; or

-   T is selected from —N(R₆)(R_(6′)); and

-   R_(6′) is    -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-cycloalkyl- or cycloalkenyl-,    -   [(C3-C10)-cycloalkyl- or cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-, or        -   wherein up to 3 aliphatic carbon atoms in each R_(6′) may be            optionally replaced with S, —S(O)—, —S(O)₂—, —O—, —N—, or            —N(H)— in a chemically stable arrangement;        -   wherein R_(6′) may be optionally substituted with up to 3 J            substituents; or        -   R₆ and R_(6′), together with the nitrogen atom to which they            are bound, may optionally form a (C3-C10)-heterocyclic ring            system wherein said ring system may be optionally            substituted with up to 3 substituents independently selected            from J.

The invention also relates to processes for preparing the abovecompounds and to compositions that comprise the above compounds and theuse thereof. Such compositions may be used to pre-treat invasive devicesto be inserted into a patient, to treat biological samples, such asblood, prior to administration to a patient, and for directadministration to a patient. In each case the composition will be usedto inhibit HCV replication and to lessen the risk of or the severity ofHCV infection.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a compound of formula I:

or a pharmaceutically acceptable salt, or mixtures thereof, wherein:

-   W is:

-   -   wherein each R₆ is independently:        -   hydrogen-,        -   (C1-C12)-aliphatic-,        -   (C6-C10)-aryl-,        -   (C6-C10)-aryl-(C1-C12)aliphatic-,        -   (C3-C10)-cycloalkyl- or cycloalkenyl-,        -   [(C3-C10)-cycloalkyl- or cycloalkenyl]-(C1-C12)-aliphatic-,        -   (C3-C10)-heterocyclyl-,        -   (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,        -   (C5-C10)-heteroaryl-, or        -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-, or        -   wherein up to 3 aliphatic carbon atoms in each R₆ may be            optionally replaced with S, —S(O)—, —S(O)₂—, —O—, —N—, or            —N(H)— in a chemically stable arrangement;        -   wherein R₆ may be optionally substituted with up to 3 J            substituents; or        -   two R₆ groups, together with the nitrogen atom to which they            are bound, may optionally form a 5- to 6-membered aromatic            or a 3- to 7-membered saturated or partially unsaturated            ring system wherein up to 3 ring atoms may be optionally            replaced with N, NH, O, S, SO, and SO₂, wherein said ring            system may be optionally fused to a (C6-C10)aryl,            (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a            (C3-C10)heterocyclyl, wherein any ring has up to 3            substituents selected independently from J;        -   wherein each R₈ is independently —OR′; or the R₈ groups            together with the boron atom, may optionally form a            (C3-C10)-membered heterocyclic ring having, in addition to            the boron, up to 3 ring atoms optionally replaced with N,            NH, O, S, SO, and SO₂;

-   J is halogen, —OR′, —NO₂, —CN, —CF₃, —OCF₃, —R′, oxo, thioxo,    ═N(R′), ═N(OR′), 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R′)₂,    —SR′, —SOR′, —SO₂R′, —SO₂N(R′)₂, —SO₃R′, —C(O)R′, —C(O)C(O)R′,    —C(O)C(O)OR′, —C(O)C(O)NR′, —C(O)CH₂C(O)R′, —C(S)R′, —C(S)OR′,    —C(O)OR′, —OC(O)R′, —C(O)N(R′)₂, —OC(O)N(R′)₂, —C(S)N(R′)₂,    —(CH₂)₀₋₂NHC(O)R′, —N(R′)N(R′)COR′, —N(R′)N(R′)C(O)OR′,    —N(R′)N(R′)CON(R′)₂, —N(R′) SO₂R′, —N(R′)SO₂N(R′)₂, —N(R′)C(O)OR′,    —N(R′)C(O)R′, —N(R′)C(S)R′, —N(R′)C(O)N(R′)₂, —N(R′)C(S)N(R′)₂,    —N(COR′)COR′, —N(OR′)R′, —C(═NH)N(R′)₂, —C(O)N(OR′)R′, —C(═NOR′)R′,    —OP(O)(OR′)₂, —P(O)(R′)₂, —P(O)(OR′)₂, or —P(O)(H)(OR′); wherein;    -   R′ is independently selected from:    -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)aliphatic-,    -   (C5-C10)-heteroaryl-, and        (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;    -   wherein up to 5 atoms in R′ may be optionally and independently        substituted with J;    -   wherein two R′ groups bound to the same atom may optionally form        a 5- to 6-membered aromatic or a 3- to 7-membered saturated or        partially unsaturated ring system wherein up to 3 ring atoms may        be optionally replaced with a heteroatom independently selected        from N, NH, O, S, SO, and SO₂, wherein said ring system may be        optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl,        (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, wherein any ring        has up to 3 substituents selected independently from J;

-   R₅ and R_(5′) are each independently hydrogen or (C1-C12)-aliphatic,    wherein any hydrogen may be optionally replaced with halogen;    wherein any terminal carbon atom of R₅ may be optionally substituted    with sulfhydryl or hydroxy; or R₅ is Ph or —CH₂Ph and R₅ is H,    wherein said Ph or —CH₂Ph group may be optionally substituted with    up to 3 substituents independently selected from J; or

-   R₅ and R_(5′) together with the atom to which they are bound may    optionally form a 3- to 6-membered saturated or partially    unsaturated ring system wherein up to 2 ring atoms may be optionally    replaced with N, NH, O, SO, or SO₂; wherein said ring system has up    to 2 substituents selected independently from J;

-   R₂, R₄, and R₇ are each independently:    -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl-(C1-C12)-aliphatic-, or    -   (C6-C10)-aryl-(C1-C12)-aliphatic-;        -   wherein up to two aliphatic carbon atoms in each of R₂, R₄,            and R₇ may be optionally replaced with S, —S(O)—, —S(O)₂—,            —O—, —N—, or —N(H)— in a chemically stable arrangement;        -   wherein each of R₂, R₄, and R₇ may be independently and            optionally substituted with up to 3 substituents            independently selected from J;

-   R₁ and R₃ are each independently:    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl- or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein up to 3 aliphatic carbon atoms in each of R₁ and R₃            may be optionally replaced with S, —S(O)—, —S(O)₂—, —O—,            —N—, or —N(H)— in a chemically stable arrangement;        -   wherein each of R₁ and R₃ may be independently and            optionally substituted with up to 3 substituents            independently selected from J;

-   R₉, R_(9′), R₁₀, and R_(10′) are each independently —X—Y-Z;

-   X is a bond, —C(H)(R₆)—, —O—, —S—, or —N(R₁₁)—;

-   R₁₁ is:    -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-cycloalkyl- or cycloalkenyl-,    -   [(C3-C10)-cycloalkyl- or cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-,        -   wherein up to 3 aliphatic carbon atoms in each R₁₁ may be            optionally replaced with S, —S(O)—, —S(O)₂—, —O—, —N—, or            —N(H)— in a chemically stable arrangement;        -   wherein R₁₁ may be optionally substituted with up to 3 J            substituents; or        -   wherein R₁₁ and Z together with the atoms to which they are            bound, optionally form a nitrogen containing 5-7-membered            mono- or 6-11-membered bicyclic ring system optionally            substituted with up to 3 J substitutents, wherein up to 3            ring atoms in said ring system may be optionally replaced            with O, NH, S, SO, or SO₂ in a chemically stable            arrangement;

-   Y is a bond, —CH₂—, —C(O)—, —C(O)C(O)—, —S(O)—, S(O)₂—, or    —S(O)(NR₁₂)—;

-   R₁₂ is:    -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-cycloalkyl- or cycloalkenyl-,    -   [(C3-C10)-cycloalkyl- or cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-,        -   wherein up to 3 aliphatic carbon atoms in each R₁₂ may be            optionally replaced with S, —S(O)—, —S(O)₂—, —O—, —N—, or            —N(H)—, in a chemically stable arrangement;        -   wherein R₁₂ may be optionally substituted with up to 3 J            substituents;

-   Z is:    -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein up to three aliphatic carbon atoms in Z may be            optionally replaced with S, —S(O)—, —S(O)₂—, —O—, —N—, or            —N(H)—, in a chemically stable arrangement;        -   wherein any ring may be optionally fused to a (C6-C10)aryl,            (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or            (C3-C10)heterocyclyl;        -   wherein Z may be independently and optionally substituted            with up to 3 substituents independently selected from J;

-   V is —C(O)—, —S(O)—, or —S(O)₂—;

-   R is —C(O)—, —S(O)—, —S(O)₂—, —N(R₁₂)—, —O—, or a bond;

-   T is:    -   (C1-C12)-aliphatic-;    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-cycloalkyl or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein up to 3 aliphatic carbon atoms in T may be replaced            with S, —S(O)—, —S(O)₂—, —O—, —N—, or —N(H)—, in a            chemically stable arrangement;        -   wherein each T may be optionally substituted with up to 3 J            substituents; or

-   T is selected from —N(R₆)(R_(6′)); and

-   R_(6′) is    -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-cycloalkyl- or cycloalkenyl-,    -   [(C3-C10)-cycloalkyl- or cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-, or        -   wherein up to 3 aliphatic carbon atoms in each R_(6′) may be            optionally replaced with S, —S(O)—, —S(O)₂—, —O—, —N—, or            —N(H)— in a chemically stable arrangement;        -   wherein R₆ may be optionally substituted with up to 3 J            substituents; or        -   R₆ and R_(6′), together with the nitrogen atom to which they            are bound, may optionally form a (C3-C10)-heterocyclic ring            system wherein said ring system may be optionally            substituted with up to 3 substituents independently selected            from J.

DEFINITIONS

The term “aryl” as used herein means a monocyclic or bicycliccarbocyclic aromatic ring system. Phenyl is an example of a monocyclicaromatic ring system. Bicyclic aromatic ring systems include systemswherein both rings are aromatic, e.g., naphthyl, and systems whereinonly one of the two rings is aromatic, e.g., tetralin. It is understoodthat as used herein, the term “(C6-C10)-aryl-” includes any one of a C6,C7, C8, C9, and C10 monocyclic or bicyclic carbocyclic aromatic ring.

The term “heterocyclyl” as used herein means a monocyclic or bicyclicnon-aromatic ring system having 1 to 3 heteroatom or heteroatom groupsin each ring selected from O, N, NH, S, SO, and SO₂ in a chemicallystable arrangement. In a bicyclic non-aromatic ring system embodiment of“heterocyclyl” one or both rings may contain said heteroatom orheteroatom groups. It is understood that as used herein, the term“(C5-C10)-heterocyclyl-” includes any one of a C5, C6, C7, C8, C9, andC10 monocyclic or bicyclic non-aromatic ring system having 1 to 3heteroatom or heteroatom groups in each ring selected from O, N, NH, andS in a chemically stable arrangement.

The term “heteroaryl” as used herein means a monocyclic or bicyclicaromatic ring system having 1 to 3 heteroatom or heteroatom groups ineach ring selected from O, N, NH, and S in a chemically stablearrangement. In such a bicyclic aromatic ring system embodiment of“heteroaryl”:

one or both rings may be aromatic; and

one or both rings may contain said heteroatom or heteroatom groups. Itis understood that as used herein, the term “(C5-C10)-heteroaryl-”includes any one of a C5, C6, C7, C8, C9, and C10 monocyclic or bicyclicaromatic ring system having 1 to 3 heteroatom or heteroatom groups ineach ring selected from O, N, NH, and S in a chemically stablearrangement.

The term “aliphatic” as used herein means a straight chained or branchedalkyl, alkenyl or alkynyl. It is understood that as used herein, theterm “(C1-C12)-aliphatic-” includes any one of a C1, C2, C3, C4, C5, C6,C7, C8, C9, C10, C11, and C12 straight or branched alkyl chain of carbonatoms. It is also understood that alkenyl or alkynyl embodiments need atleast two carbon atoms in the aliphatic chain. The term “cycloalkyl orcycloalkenyl” refers to a monocyclic or fused or bridged bicycliccarbocyclic ring system that is not aromatic. Cycloalkenyl rings haveone or more units of unsaturation. It is also understood that as usedherein, the term “(C3-C10)-cycloalkyl- or -cycloalkenyl-” includes anyone of a C3, C4, C5, C6, C7, C8, C9, and C10 monocyclic or fused orbridged bicyclic carbocyclic ring. Preferred cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,cycloheptyl, cycloheptenyl, norbornyl, adamantyl and decalin-yl.

The phrase “chemically stable arrangement” as used herein refers to acompound structure that renders the compound sufficiently stable toallow manufacture and administration to a mammal by methods known in theart. Typically, such compounds are stable at a temperature of 40° C. orless, in the absence of moisture or other chemically reactive condition,for at least a week.

EMBODIMENTS

According to one embodiment of compounds of formula I, the

radical is,

wherein;in R′, R₁₀, and R_(10′), X and Y are both a bond and Z is hydrogen; andin R_(9′);X is a bond;Y is a bond, —CH₂—, or —C(O)—; andZ is (C1-C12)-aliphatic-,

-   -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein up to three aliphatic carbon atoms in Z may be            optionally replaced with S, —S(O)—, —S(O)₂—, —O—, —N—, or            —N(H)—, in a chemically stable arrangement;        -   wherein any ring may be optionally fused to a (C6-C10)aryl,            (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or            (C3-C10)heterocyclyl;        -   wherein Z may be independently and optionally substituted            with up to 3 substituents independently selected from J.

According to another embodiment, in R_(9′);

X is a bond;Y is a bond; andZ is (C1-C12)-aliphatic-,

-   -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein up to three aliphatic carbon atoms in Z may be            optionally replaced with S, —S(O)—, —S(O)₂—, —O—, —N—, or            —N(H)—, in a chemically stable arrangement;        -   wherein any ring may be optionally fused to a (C6-C10)aryl,            (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or            (C3-C10)heterocyclyl;        -   wherein Z may be independently and optionally substituted            with up to 3 substituents independently selected from J.

According to another embodiment, in R_(9′);

X is a bond;Y is a bond; andZ is (C1-C12)-aliphatic-,

-   -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-, or    -   (C6-C10)-aryl-(C1-C12)aliphatic-,        -   wherein up to three aliphatic carbon atoms in Z may be            optionally replaced with S, —S(O)—, —S(O)₂—, —O—, —N—, or            —N(H)—, in a chemically stable arrangement;        -   wherein Z may be independently and optionally substituted            with up to 3 substituents independently selected from J.

According to another embodiment, R_(9′) is

According to another embodiment, R_(9′) is

According to another embodiment, R_(9′) is ethyl.

According to another embodiment of compounds of formula I, in R₉, R₁₀,and R_(10′), X and Y are both a bond and Z is hydrogen; and in R_(9′);

X is a bond;

Y is —C(O)—; and

Z is (C1-C12)-aliphatic-, or

-   -   (C3-C10)-heterocyclyl-(C1-C12)aliphatic-;        -   wherein up to three aliphatic carbon atoms in Z may be            optionally replaced with S, —S(O)—, —S(O)₂—, —O—, —N—, or            —N(H)—, in a chemically stable arrangement;        -   wherein any ring may be optionally fused to a (C6-C10)aryl,            (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or            (C3-C10)heterocyclyl;        -   wherein Z may be independently and optionally substituted            with up to 3 substituents independently selected from J.

According to another embodiment, Z is —O—(C1-C6)-aliphatic or —N(R′)₂,wherein the two R′ groups bound to the nitrogen atom may optionally forma 3- to 7-membered saturated or partially unsaturated ring systemwherein up to 3 ring atoms may be optionally replaced with a heteroatomindependently selected from N, NH, O, S, SO, and SO₂, wherein said ringsystem may be optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl,(C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, wherein any ring has upto 3 substituents selected independently from J.

According to another embodiment of compounds of formula I, Z is —N(R′)₂,wherein the two R′ groups bound to the nitrogen atom may optionally forma 3- to 7-membered saturated or partially unsaturated ring systemwherein up to 3 ring atoms may be optionally replaced with a heteroatomindependently selected from N, NH, O, S, SO, and SO₂, wherein said ringsystem may be optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl,(C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, wherein any ring has upto 3 substituents selected independently from J.

According to another embodiment of compounds of formula I, in R₉, andR₁₀, X and Y are both a bond and Z is hydrogen; and in each of R_(9′)and R_(10′) independently,

X is a bond;Y is a bond; andZ is (C1-C12)-aliphatic-,

-   -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C3-C10)-heterocyclyl-(C1-C12)aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;        -   wherein up to three aliphatic carbon atoms in Z may be            optionally replaced with S, —S(O)—, —S(O)₂—, —O—, —N—, or            —N(H)—, in a chemically stable arrangement;        -   wherein any ring may be optionally fused to a (C6-C10)aryl,            (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or            (C3-C10)heterocyclyl;        -   wherein Z may be independently and optionally substituted            with up to 3 substituents independently selected from J.

According to another embodiment, Z in each of R_(9′) and R_(10′)independently, is

-   -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-, or    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-;        -   wherein up to three aliphatic carbon atoms in Z may be            optionally replaced with S, —S(O)—, —S(O)₂—, —O—, —N—, or            —N(H)—, in a chemically stable arrangement;        -   wherein Z may be independently and optionally substituted            with up to 3 substituents independently selected from J.

According to another embodiment Z, in each of R_(9′), and R_(10′),independently is (C1-C6)-aliphatic-.

According to another embodiment of compounds of formula I, in R₁₀, andR_(10′), X and Y are both a bond and Z is hydrogen; and in R₉ andR_(9′);

X is a bond,Y is a bond, andZ is (C1-C6)-aliphatic-,

-   -   wherein Z may be independently and optionally substituted with        up to 3 substituents independently selected from J.

According to another embodiment of compounds of formula I, W is:

wherein in the W, the NR₆R₆ is selected from —NH— (C1-C6 aliphatic),—NH— (C3-C6 cycloalkyl), —NH—CH(CH₃)-aryl, or —NH—CH(CH₃)-heteroaryl,wherein said aryl or said heteroaryl is optionally substituted with upto 3 halogens.

According to another embodiment in the W, the NR₆R₆ is:

According to another embodiment in the W, the NR₆R₆ is:

According to another embodiment in the W, the NR₆R₆ is:

According to another embodiment in the W, the NR₆R₆ is:

According to another embodiment in compounds of formula I, the NR₆R₆ inthe W radical is:

According to another embodiment, the NR₆R₆ in the W radical is:

According to another embodiment, in the W, the NR₆R₆ is:

According to another embodiment W in compounds of formula I is:

wherein R₈ is as defined above.

According to another embodiment each R₈ together with the boron atom, isa (C5-C10)-membered heterocyclic ring having no additional heteroatomsother than the boron and the two oxygen atoms.

In another embodiment W is:

wherein R′ is (C1-C6)-aliphatic.

In another embodiment R′ is methyl.

According to another embodiment of compounds of formula I, R_(5′) ishydrogen and R₅ is:

According to another embodiment R_(5′) is hydrogen and R₅ is:

According to another embodiment in compounds of formula I, R_(5′) and R₅is:

According to another embodiment of compounds of formula I, R₂, R₄, andR₇ are each independently H, methyl, ethyl, or propyl.

According to another embodiment R₂, R₄, and R₇ are each hydrogen.

According to another embodiment of compounds of formula I, R₃ is:

According to another embodiment R₃ is:

According to another embodiment R₃ is:

According to another embodiment of compounds of formula I, R₁ is:

According to another embodiment R₁ is:

According to another embodiment wherein R₁ is isopropyl or cyclohexyl.

According to another embodiment of compounds of formula I, the

radical is:

wherein:

R₆, R_(6′), R₇, and R₁₂, are as defined in any of the embodimentsherein.

According to another embodiment in the

radical;

R_(6′) and R₇ are both hydrogen;

R₆ is:

(C1-C12)-aliphatic-;

(C6-C10)-aryl-,

(C6-C10)-aryl-(C1-C12)aliphatic-,

(C3-C10)-cycloalkyl or -cycloalkenyl-,

[(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,

(C3-C10)-heterocyclyl-,

(C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,

(C5-C10)-heteroaryl-, or

(C5-C10)-heteroaryl-(C1-C12)-aliphatic-;

-   -   wherein up to 3 aliphatic carbon atoms in R₆ may be optionally        replaced by S, —S(O)—, —S(O)₂—, —O—, —N—, or —N(H)—, in a        chemically stable arrangement; and    -   wherein R₆ may be optionally substituted with up to 3        substituents independently selected from J; and        R₁₂ is as defined in any of the embodiments herein.

According to another embodiment

R₆ is:

(C1-C12)-aliphatic-;

(C6-C10)-aryl-(C1-C12)aliphatic-, or

(C3-C10)-cycloalkyl or -cycloalkenyl-;

-   -   wherein up to 3 aliphatic carbon atoms in R₆ may be optionally        replaced by S, —S(O)—, —S(O)₂—, —O—, —N—, or —N(H)—, in a        chemically stable arrangement;    -   wherein R₆ may be optionally substituted with up to 3        substituents independently selected from J; and        R₁₂ is as defined in any of the embodiments herein.

According to another embodiment the radical is:

According to another embodiment the

radical is:

According to another embodiment of compounds of formula I, V is —C(O)—and R is a bond.

According to another embodiment of compounds of formula I, V is —C(O)—,R is a bond, and

T is:

(C3-C10)-heterocyclyl- or (C5-C10)heteroaryl-;

-   -   wherein each T is optionally substituted with up to 3 J        substituents.

According to another embodiment, T is

(C5-C6)heterocyclyl- or (C5-C6)heteroaryl-;

-   -   wherein each T is optionally substituted with up to 3 J        substituents.

According to another embodiment, T is:

wherein:

Z′ is independently O, S, NR′, or C(R′)₂.

According to another embodiment, T is:

According to another embodiment, this invention does not include thefollowing compounds:

-   1. 3-Acetyl-4,5-dimethyl-1H-pyrrole-2-carboxylic acid    (cyclohexyl-{1-[3-cyclohexyl-2-(1-cyclopropylaminooxalyl-butylcarbamoyl)-pyrrolidine-1-carbonyl]-2,2-dimethyl-propylcarbamoyl}-methyl)-amide;-   2. 3-Acetyl-4,5-dimethyl-1H-pyrrole-2-carboxylic acid    (cyclohexyl-{1-[2-(1-cyclopropylaminooxalyl-butylcarbamoyl)-3-isopropyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propylcarbamoyl}-methyl)-amide;-   3. 3-Acetyl-4,5-dimethyl-1H-pyrrole-2-carboxylic acid    (cyclohexyl-{1-[2-(1-cyclopropylaminooxalyl-butylcarbamoyl)-4-(quinazolin-4-yloxy)-pyrrolidine-1-carbonyl]-2,2-dimethyl-propylcarbamoyl}-methyl)-amide;    and-   4. 3-Acetyl-4,5-dimethyl-1H-pyrrole-2-carboxylic acid    ({1-[4-(5-chloro-pyridin-2-yloxy)-2-(1-cyclopropylaminooxalyl-butylcarbamoyl)-pyrrolidine-1-carbonyl]-2,2-dimethyl-propylcarbamoyl}-cyclohexyl-methyl)-amide    (e.g., compounds 63, 64, 66, and 67 of WO 03/087092).

According to yet another embodiment, this invention does not include thefollowing compounds

wherein:V is —C(O)—, R is a bond, T is the (C5-C10)-heteroaryl3-acetyl-4,5-dimethyl-1H-pyrrole and the

radical is:

(e.g., substituted proline radicals at pages 56 and 57 of WO 03/087092).

According to another embodiment, this invention does not includecompounds wherein:

V is —C(O)—;

R is a bond; andT is 3-acetyl-4,5-dimethyl-1H-pyrrole (e.g., compounds of formula II″ atpage 85 of WO 03/087092).

According to another embodiment, this invention does not includecompounds wherein T is a C5-heteroaryl (e.g., compounds of formula II atpage 22 of WO 03/087092).

According to another embodiment, this invention does not includecompounds wherein T is an optionally substituted pyrrole group (e.g.,compounds of formula II at page 22 of WO 03/087092).

According to another embodiment, this invention does not includecompounds wherein:

V is —C(O)—, —S(O)—, or —S(O)₂—;

R is a bond; and

T is:

wherein:

R₁₄ is —H, —S(O)R′, —S(O)₂R′, —C(O)R′, —C(O)OR′, —C(O)N(R′)₂,—N(R′)C(O)R′, —N(COR′)COR′, —SO₂N(R′)₂, —SO₃R′, —C(O)C(O)R′,—C(O)CH₂C(O)R′, —C(S)R′, —C(S)N(R′)₂, —(CH₂)₀₋₂NHC(O)R′,—N(R′)N(R′)COR′, —N(R′)N(R′)C(O)OR′, —N(R′)N(R′)CON(R′)₂, —N(R′)SO₂R′,—N(R′) SO₂N(R′)₂, —N(R′)C(O)OR′, —N(R′)C(O)R′, —N(R′)C(S)R′,—N(R′)C(O)N(R′)₂, —N(R′)C(S)N(R′)₂, —N(COR′)COR′, —N(OR′)R′,—C(═NH)N(R′)₂, —C(O)N(OR′)R′, —C(═NOR′)R′, —OP(O)(OR′)₂, —P(O)(R′)₂,—P(O)(OR′)₂, or —P(O)(H)(OR′);

R₁₅ and R₁₆ are independently halogen, —OR′, —OC(O)N(R′)₂, —NO₂, —CN,—CF₃, —OCF₃, —R′, oxo, 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R′)₂,—SR′, —SOR′, —SO₂R′, —SO₂N(R′)₂, —SO₃R′, —C(O)R′, —C(O)C(O)R′,—C(O)CH₂C(O)R′, —C(S)R′, —C(O)OR′, —OC(O)R′, —C(O)N(R′)₂, —OC(O)N(R′)₂,—C(S)N(R′)₂, —(CH₂)₀₋₂NHC(O)R′, —N(R′)N(R′)COR′, —N(R′)N(R′)C(O)OR′,—N(R′)N(R′)CON(R′)₂, —N(R′)SO₂R′, —N(R′)SO₂N(R′)₂, —N(R′)C(O)OR′,—N(R′)C(O)R′, —N(R′)C(S)R′, —N(R′)C(O)N(R′)₂, —N(R′)C(S)N(R′)₂,—N(COR′)COR′, —N(OR′)R′, —CN, —C(═NH)N(R′)₂, —C(O)N(OR′)R′, —C(═NOR′)R′,—OP(O)(OR′)₂, —P(O)(R′)₂, —P(O)(OR′)₂, or —P(O)(H)(OR′);

Z₂ is ═O, ═NR′, ═NOR′, or ═C(R′)₂;

R₁₉ is —OR′, —CF₃, —OCF₃, —R′, —N(R′)₂, —SR′, —C(O)R′, —COOR′,—CON(R′)₂, —N(R′)COR′, or —N(COR′)COR′; wherein

two R′ groups together with the atoms to which they are bound form a 3-to 10-membered aromatic or non-aromatic ring having up to 3 heteroatomsindependently selected from N, NH, O, S, SO, or SO₂, wherein the ring isoptionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl,(C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, and wherein any ring hasup to 3 substituents selected independently from J₂; or

each R′ is independently selected from:

-   -   hydrogen-,    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C6-C10)-heterocyclyl-(C1-C12)aliphatic-,    -   (C5-C10)-heteroaryl-, or    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-,        wherein R′ has up to 3 substituents selected independently from        J₂; and

J₂ is halogen, —OR′, —OC(O)N(R′)₂, —NO₂, —CN, —CF₃, —OCF₃, —R′, oxo,thioxo, 1,2-methylenedioxy, —N(R′)₂, —SR′, —SOR′, —SO₂R′, —SO₂N(R′)₂,—SO₃R′, —C(O)R′, —C(O)C(O)R′, —C(O)CH₂C(O)R′, —C(S)R′, —C(O)OR′,—OC(O)R′, —C(O)N(R′)₂, —OC(O)N(R′)₂, —C(S)N(R′)₂, —(CH₂)₀₋₂NHC(O)R′,—N(R′)N(R′)COR′, —N(R′)N(R′)C(O)OR′, —N(R′)N(R′)CON(R′)₂, —N(R′)SO₂R′,—N(R′)SO₂N(R′)₂, —N(R′)C(O)OR′, —N(R′)C(O)R′, —N(R′)C(S)R′,—N(R′)C(O)N(R′)₂, —N(R′)C(S)N(R′)₂, —N(COR′)COR′, —N(OR′)R′, —CN,—C(═NH)N(R′)₂, —C(O)N(OR′)R′, —C(═NOR′)R′, —OP(O)(OR′)₂, —P(O)(R′)₂,—P(O)(OR′)₂, or —P(O)(H)(OR′) (e.g., compounds of formula II at page 22of WO 03/087092).

According to another preferred embodiment in compounds of formula I, thecompound is:

The compounds of this invention may contain one or more asymmetriccarbon atoms and thus may occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. All such isomeric forms of these compounds are expresslyincluded in the present invention. Each stereogenic carbon may be of theR or S configuration.

In another embodiment, the compounds of this invention have thestructure and stereochemistry depicted in compounds 1-77.

Any of the embodiments recited above, including those embodiments in theabove species, may be combined to produce a preferred embodiment of thisinvention.

As can be appreciated by the skilled artisan, the synthetic schemesshown are not intended to comprise a comprehensive list of all means bywhich the compounds described and claimed in this application may besynthesized. Other equivalent schemes, which will be readily apparent tothe ordinary skilled organic chemist, may alternatively be used tosynthesize various portions of the molecule as illustrated by thegeneral schemes below. Additionally, the various synthetic stepsdescribed above may be performed in an alternate sequence or order togive the desired compounds. Other equivalent schemes, which will bereadily apparent to the ordinary skilled organic chemist, mayalternatively be used to synthesize various portions of the molecule asillustrated by the general schemes below, and the preparative examplesthat follow.

Abbreviations which are used in the schemes, preparations and theexamples that follow are:

-   DCM: dichloromethane-   THF: tetrahydrofuran-   DMF: N,N,-dimethylformamide-   EtOAc: ethyl acetate-   AcOH: acetic acid-   NMM: N-methylmorpholine-   NMP: N-methylpyrrolidinone-   EtOH: ethanol-   t-BuOH: tert-butanol-   Et₂O: diethyl ether-   DMSO: dimethyl sulfoxide-   DCCA: dichloroacetic acid-   DIEA: diisopropylethylamine-   MeCN: acetonitrile-   TFA: trifluoroacetic acid-   DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene-   DEAD: diethyl azodicarboxylate-   HOBt: 1-hydroxybenzotriazole hydrate-   HOAt: 1-hydroxy-7-azabenzotriazole-   EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-   Boc: tert-butyloxycarbonyl-   Boc₂O: di-tert-butyldicarbonate-   Cbz: benzyloxycarbonyl-   Cbz-Cl: benzyl chloroformate-   Fmoc: 9-fluorenyl methyloxycarbonyl-   SEM: silylethoxymethyl-   TBAF: tetrabutylammonium fluoride-   Chg: cyclohexylglycine-   t-BG: tert-butylglycine-   mCBPA: 3-chloroperoxybenzoic acid-   DAST: (diethylamino)sulfur trifluoride-   TEMPO: 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical-   PyBOP: tris(pyrrolidino)bromophosphonium hexafluorophosphate-   TBTU or HATU: 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium    tetrafluoroborate-   DMAP: 4-dimethylaminopyridine-   AIBN: 2,2′-azobisisobutyronitrile-   rt or RT: room temperature-   ON: overnight-   ND: not determined-   MS: mass spectrometry-   LC: liquid chromatography

General Synthetic Methodology:

The compounds of this invention may be prepared in general by methodsknown to those skilled in the art. Schemes 1-6 below illustratesynthetic routes to the compounds of the present invention. Otherequivalent schemes, which will be readily apparent to the ordinaryskilled organic chemist, may alternatively be used to synthesize variousportions of the molecule as illustrated by the general schemes below,and the preparative examples that follow.

Scheme 1-6 above provide synthetic pathways for the preparation of thecompounds of this invention. Many of the starting proline derivativesmay be purchased commercially from chemical suppliers known to those inthe art. Intermediate A1 may be prepared according to the proceduredescribed in J. Med. Chem. 39, p. 2367 (1996).

Although certain embodiments are depicted and described below, it willbe appreciated that compounds of this invention can be preparedaccording to the methods described generally above using appropriatestarting materials generally available to one of ordinary skill in theart.

Another embodiment of this invention provides a pharmaceuticalcomposition comprising a compound of formula I or a pharmaceuticallyacceptable salt thereof. According to another embodiment, the compoundof formula I is present in an amount effective to decrease the viralload in a sample or in a patient, wherein said virus encodes a serineprotease necessary for the viral life cycle, and a pharmaceuticallyacceptable carrier.

If pharmaceutically acceptable salts of the compounds of this inventionare utilized in these compositions, those salts are preferably derivedfrom inorganic or organic acids and bases. Included among such acidsalts are the following: acetate, adipate, alginate, aspartate,benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate,camphor sulfonate, cyclopentane-propionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate,pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.Base salts include ammonium salts, alkali metal salts, such as sodiumand potassium salts, alkaline earth metal salts, such as calcium andmagnesium salts, salts with organic bases, such as dicyclohexylaminesalts, N-methyl-D-glucamine, and salts with amino acids such asarginine, lysine, and so forth.

Also, the basic nitrogen-containing groups may be quaternized with suchagents as lower alkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides and iodides; dialkyl sulfates, such as dimethyl,diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkylhalides, such as benzyl and phenethyl bromides and others. Water oroil-soluble or dispersible products are thereby obtained.

The compounds utilized in the compositions and methods of this inventionmay also be modified by appending appropriate functionalities to enhanceselective biological properties. Such modifications are known in the artand include those which increase biological penetration into a givenbiological system (e.g., blood, lymphatic system, central nervoussystem), increase oral availability, increase solubility to allowadministration by injection, alter metabolism and alter rate ofexcretion.

Pharmaceutically acceptable carriers that may be used in thesecompositions include, but are not limited to, ion exchangers, alumina,aluminum stearate, lecithin, serum proteins, such as human serumalbumin, buffer substances such as phosphates, glycine, sorbic acid,potassium sorbate, partial glyceride mixtures of saturated vegetablefatty acids, water, salts or electrolytes, such as protamine sulfate,disodium hydrogen phosphate, potassium hydrogen phosphate, sodiumchloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

According to another embodiment, the compositions of this invention areformulated for pharmaceutical administration to a mammal. In anotherembodiment the compositions of this invention are formulated forpharmaceutical administration to a human being.

Such pharmaceutical compositions of the present invention may beadministered orally, parenterally, by inhalation spray, topically,rectally, nasally, buccally, vaginally or via an implanted reservoir.The term “parenteral” as used herein includes subcutaneous, intravenous,intramuscular, intra-articular, intra-synovial, intrasternal,intrathecal, intrahepatic, intralesional and intracranial injection orinfusion techniques. In another embodiment, the compositions areadministered orally or intravenously.

Sterile injectable forms of the compositions of this invention may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such ascarboxymethyl cellulose or similar dispersing agents which are commonlyused in the formulation of pharmaceutically acceptable dosage formsincluding emulsions and suspensions. Other commonly used surfactants,such as Tweens, Spans and other emulsifying agents or bioavailabilityenhancers which are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation.

Dosage levels of between about 0.01 and about 100 mg/kg body weight perday, preferably between about 0.5 and about 75 mg/kg body weight per dayof the protease inhibitor compounds described herein are useful in amonotherapy for the prevention and treatment of antiviral, particularlyanti-HCV mediated disease. Typically, the pharmaceutical compositions ofthis invention will be administered from about 1 to about 5 times perday or alternatively, as a continuous infusion. Such administration canbe used as a chronic or acute therapy. The amount of active ingredientthat may be combined with the carrier materials to produce a singledosage form will vary depending upon the host treated and the particularmode of administration. A typical preparation will contain from about 5%to about 95% active compound (w/w). In another embodiment, suchpreparations contain from about 20% to about 80% active compound.

When the compositions of this invention comprise a combination of acompound of formula I and one or more additional therapeutic orprophylactic agents, both the compound and the additional agent shouldbe present at dosage levels of between about 10 to 100% and in anotherembodiment between about 10 to 80% of the dosage normally administeredin a monotherapy regimen.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers that are commonly used includelactose and corn starch. Lubricating agents, such as magnesium stearate,are also typically added. For oral administration in a capsule form,useful diluents include lactose and dried cornstarch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of this invention may beadministered in the form of suppositories for rectal administration.These may be prepared by mixing the agent with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract may be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions may be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith our without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

In another embodiment, the pharmaceutical compositions are formulatedfor oral administration.

In one embodiment, the compositions of this invention additionallycomprise another agent, including a cytochrome P-450 inhibitor. Suchcytochrome P-450 inhibitors include, but are not limited to, ritonavir.

In another embodiment, the compositions of this invention additionallycomprise another anti-viral agent, including an anti-HCV agent. Suchanti-viral agents include, but are not limited to, immunomodulatoryagents, such as α-, β-, and γ-interferons, pegylated derivatizedinterferon-α compounds, and thymosin; other anti-viral agents, such asribavirin, amantadine, and telbivudine; other inhibitors of hepatitis Cproteases (NS2-NS3 inhibitors and NS3-NS4A inhibitors); inhibitors ofother targets in the HCV life cycle, including but not limited to,helicase and polymerase inhibitors; inhibitors of internal ribosomeentry; broad-spectrum viral inhibitors, such as IMPDH inhibitors (e.g.,VX-497 and other IMPDH inhibitors disclosed in U.S. Pat. Nos. 5,807,876and 6,498,178, mycophenolic acid and derivatives thereof); inhibitors ofcytochrome P-450, such as ritonavir, or combinations of any of theabove.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level, treatment should cease.Patients may, however, require intermittent treatment on a long-termbasis upon any recurrence of disease symptoms.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of active ingredients will also depend upon the particulardescribed compound and the presence or absence and the nature of theadditional anti-viral agent in the composition.

According to another embodiment, the invention provides a method fortreating a patient infected with a virus characterized by a virallyencoded serine protease that is necessary for the life cycle of thevirus by administering to said patient a pharmaceutically acceptablecomposition of this invention. In another embodiment, the methods ofthis invention are used to treat a patient suffering from a HCVinfection. Such treatment may completely eradicate the viral infectionor reduce the severity thereof. In another embodiment, the methods ofthis invention are used to treat a patient suffering from a HCVinfection wherein the patient is a human being.

In an alternate embodiment, the methods of this invention additionallycomprise the step of administering to said patient an anti-viral agentpreferably an anti-HCV agent. Such anti-viral agents include, but arenot limited to, immunomodulatory agents, such as α-, β-, andγ-interferons, pegylated derivatized interferon-α compounds, andthymosin; other anti-viral agents, such as ribavirin, amantadine, andtelbivudine; other inhibitors of hepatitis C proteases (NS2-NS3inhibitors and NS3-NS4A inhibitors); inhibitors of other targets in theHCV life cycle, including helicase and polymerase inhibitors; inhibitorsof internal ribosome entry; broad-spectrum viral inhibitors, such asIMPDH inhibitors (e.g., VX-497 and other IMPDH inhibitors disclosed inU.S. Pat. Nos. 5,807,876 and 6,498,178, mycophenolic acid andderivatives thereof); inhibitors of cytochrome P-450, such as ritonavir,or combinations of any of the above.

Such additional agent may be administered to said patient as part of asingle dosage form comprising both a compound of this invention and anadditional anti-viral agent. Alternatively the additional agent may beadministered separately from the compound of this invention, as part ofa multiple dosage form, wherein said additional agent is administeredprior to, together with or following a composition comprising a compoundof this invention.

In yet another embodiment the present invention provides a method ofpre-treating a biological substance intended for administration to apatient comprising the step of contacting said biological substance witha pharmaceutically acceptable composition comprising a compound of thisinvention. Such biological substances include, but are not limited to,blood and components thereof such as plasma, platelets, subpopulationsof blood cells and the like; organs such as kidney, liver, heart, lung,etc; sperm and ova; bone marrow and components thereof, and other fluidsto be infused into a patient such as saline, dextrose, etc.

According to another embodiment the invention provides methods oftreating materials that may potentially come into contact with a viruscharacterized by a virally encoded serine protease necessary for itslife cycle. This method comprises the step of contacting said materialwith a compound according to the invention. Such materials include, butare not limited to, surgical instruments and garments (e.g. clothes,gloves, aprons, gowns, masks, eyeglasses, footwear, etc.); laboratoryinstruments and garments (e.g. clothes, gloves, aprons, gowns, masks,eyeglasses, footwear, etc.); blood collection apparatuses and materials;and invasive devices, such as shunts, stents, etc.

In another embodiment, the compounds of this invention may be used aslaboratory tools to aid in the isolation of a virally encoded serineprotease. This method comprises the steps of providing a compound ofthis invention attached to a solid support; contacting said solidsupport with a sample containing a viral serine protease underconditions that cause said protease to bind to said solid support; andeluting said serine protease from said solid support. In anotherembodiment, the viral serine protease isolated by this method is HCVNS3-NS4A protease.

In order that this invention be more fully understood, the followingpreparative and testing examples are set forth. These examples are forthe purpose of illustration only and are not to be construed as limitingthe scope of the invention in any way.

EXAMPLES

¹H-NMR spectra were recorded at 500 MHz using a Bruker AMX 500instrument. Mass spec. samples were analyzed on a MicroMass ZQ orQuattro II mass spectrometer operated in single MS mode withelectrospray ionization. Samples were introduced into the massspectrometer using flow injection (FIA) or chromatography. Mobile phasefor all mass spec. analysis consisted of acetonitrile-water mixtureswith 0.2% formic acid as a modifier.

As used herein, the term “R_(t)(min)” refers to the HPLC retention time,in minutes, associated with the compound. The HPLC retention timeslisted were either obtained from the mass spec. data or using thefollowing method:

-   Instrument: Hewlett Packard HP-1050;-   Column: YMC C18 (Cat. No. 326289C46);-   Gradient/Gradient Time: 10-90% CH₃CN/H2O over 9 minutes, then 100%    CH₃CN for 2 minutes;-   Flow Rate: 0.8 ml/min;-   Detector Wavelength: 215 nM and 245 nM.

Chemical naming for selected compounds herein was accomplished using thenaming program provided by CambridgeSoft Corporations ChemDraw Ultra®,version 7.0.1.

Example 1 Pyrazine-2-carboxylic acid(cyclohexyl-{1-[2-(1-cyclopropylaminooxalyl-butylcarbamoyl)-3-isopropyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propylcarbamoyl}-methyl)-amide(56)

To a stirring suspension of copper bromide-dimethylsulfide (9.1 g, 44.28mmol) in 100 mL of dry ether at −20° C. was added isopropenyl magnesiumbromide 0.09M (100 mL). After 15 min. of stirring, the temperature waslowered to −78° C. and enone 4a (4.0 g, 8.86 mmol, prepared according toprocedure in JACS, 117, p. 10775, (1995)) in 50 mL of ether was addedfollowed by TMSCl (2.25 mL, 18 mmol). The reaction mixture was stirredat −78° C. for 1 h and quenched with 100 mL of ammoniumhydroxide-ammonium chloride solution (1:4). Extracted with ether and theorganic phase was washed to remove all the copper salts. The ether layerwas dried with sodium sulfate and concentrated in vacuo to an oil thatwas subjected to flash chromatography (ether-hexanes (2:3) to provide3.5 g (73%) of the desired intermediate olefin.

¹H NMR (CDCl₃) δ 4.8 (d, 2H); 3.8 (m, 2H); 3.7 (d, 1H); 2.8 (m, 2H); 2.2(d, 1H); 1.7 (s, 3H); 1.5 (s, 9H); 0.8 (s, 9H); 0.1 (s, 3H); 0.08 (s,3H) ppm.

Hydrogenation with 10% Pd—C under 1 atmosphere of hydrogen provided 3.5g (100%) of the desired proline 5b.

HCl gas was bubbled 5 minutes to a solution of 5b (3.5 g, 6.47 mmol) in50 mL of ethyl acetate at −20° C. Stirred at −20° C. for 30 minutes thenwarmed up at rt and stirred for 1 h. It was concentrated in vacuo to1.71 g (100%)of an oil that was reduced with 2.5 equivalent of a 1M LAHin THF solution under reflux for 4 h. Cooled and subjected to a Fieserwork up which provided 1.35 g (85%) of the desired compound 8b. ¹H NMR(CDCl₃) δ 4.0 (dd, 1H); 3.6 (m, 1H); 3.4 (m, 1H); 3.3 (m, 1H); 3.2 (m,1H); 2.2 (m, 1H); 1.8 (m, 3H); 1.0 (d, 3H); 0.9 (d, 3H) ppm.

To a solution of potassium carbonate (190 mg, 1.38 mmol) in 4 mL ofwater at rt with stirring, was added 8b (357 mg, 2.5 mmol) in 5 mL ofTHF. The solution was cooled to −2° C. and Cbz chloride (0.447 mL, 3.13mmol) was added dropwise maintaining the temperature at 0 to −2° C. Itwas stirred for an additional 15 minutes, poured into water-ice. Theaqueous phase was saturated with salt and the organic phase separated.Further extraction with ethyl acetate was necessary to extract all thecompound. The combined organics were washed with HCl 5%, water andbrine, dried with sodium sulfate and concentrated in vacuo to 416 mg(60%) on benzoylated hydroxymethylpyrrolidine intermediate. 328 mg ofthis material was oxidized with Jones reagent to provide 260 mg (75%) ofthe proline intermediate. The above proline (260 mg, 0.889 mmol) wasesterified with isobutylene in dichloromethane with a catalytic amountof concentrated sulfuric acid at rt in a seal vessel for 48 h to provide289 mg (96%) of the intermediate ester. ¹H NMR (CDCl₃) δ 7.5 (m, 5H);5.1 (m, 2H); 4.1 (dd, 1H); 3.6 (m, 1H); 3.5 (m, 1H); 2.1 (m, 2H); 1.7(m, 2H); 1.5 (s, 9H); 1.1 (d, 3H); 1.0 (d, 3H) ppm.

Hydrogenation with 10% Pd/C in ethyl acetate gave 290 mg (100%) of thedesired compound 9b.

To a solution of Cbz-tert-butyl glycine (271 mg, 1.02 mmol) in 2 mL ofDCM at 0° C. was added EDC (235 mg, 1.23 mmol), HOBt (203 mg, 1.33 mmol)and DIEA (0.534 mL, 3.07 mmol). The resulting mixture was stirred at 0°C. for 15 min. after which, the above amino ester 9b was slowly added in2 mL of DCM. The resulting reaction mixture was stirred at rt for 16 h.Concentrated to a residue that was redissolved in EtOAc. Successivewashes with 0.5N HCL, satd' aqueous NaHCO₃ and brine gave after drying(Na₂SO₄) and concentration in vacuo the desired product which wassubjected to flash chromatography (20% EtOAc/80% hexanes) to provide 480mg (100%) of pure dipeptide. ¹H NMR (CDCl₃) δ 4.2 (d, 2H); 4.0 (t, 1H);3.5 (m, 1H); 2.0 (m, 3H0; 2.8 (m, 2H); 1.5 (s, 9H); 1.1 (s, 9H); 1.0 (d,3H); 0.9 (d, 3H) ppm.

The Cbz group of the dipeptide was removed as described above and theresulting aminoester dipeptide was coupled to Cbz-cyclohexyl glycineshown in the next step.

To a solution of Cbz-cyclohexyl glycine (289 mg, 1 mmol) in 2 mL of DCMat 0° C. was added EDC (228 mg, 1.19 mmol), HOBt (190 mg, 1.29 mmol) andDIEA (0.517 mL, 2.97 mmol). The resulting mixture was stirred at 0° C.for 15 min. after which, the above amino ester was slowly added in 2 mLof DCM. The resulting reaction mixture was stirred at rt for 16 h.Concentrated to a residue that was redissolved in EtOAc. Successivewashes with 0.5N HCL, satd' aqueous NaHCO₃ and brine gave after drying(Na₂SO₄) and concentration in vacuo the desired product which wassubjected to flash chromatography (20% EtOAc/80% hexanes) to provide 556mg (90%) of pure tripeptide. The Cbz group of the tripeptide was removedas described above and the resulting aminoester tripeptide was coupledto 1,4-pyrazine carboxylic acid shown in the next step.

To a solution of 1,4-pyrazine carboxylic acid (110 mg, 0.891 mmol)) in 2mL of DCM was added PyBrOP (457 mg, 0.98 mmol and DIEA (0.465 mL, 2.67mmol). The resulting mixture was stirred at rt for 15 min. after which,the above amino ester was slowly added in 2 mL of DCM. The resultingreaction mixture was stirred at rt for 16 h. Concentrated to a residuethat was redissolved in EtOAc. Successive washes with 0.5N HCL, sat'daqueous NaHCO₃ and brine gave after drying (Na₂SO₄) and concentration invacuo the desired product which was subjected to flash chromatography(50% EtOAc/50% hexanes) to provide 410 mg (79%) of pure cappedtripeptide with consistent ¹H NMR (CDCl₃).

The t-butyl ester group of the capped tripeptide (410 mg, 0.688 mmol)was cleaved with a 1:1 mixture of TFA-DCM at rt for 45 minutes andconcentrated in vacuo. The resulting aminoester tripeptide was coupledto hydroxyamide detailed in the next step.

To a stirring solution of the capped tripeptide acid from above in 6 mLof dry DMF at 0° C. was added, PyBOP (376 mg, 0.722 mmol) followed byNMM (0.226 mL, 2.06 mmol). The reaction mixture was stirred for 1 h atrt after which a solution of hydroxyamide (168 mg, 0.758 mmol) and 0.226mL of NMM was slowly added. The coupling reaction was stirred for 16 h,diluted with ethyl acetate and was successively washed with; water (3×),citric acid 10%, water and brine. The organic layer was dried (Na₂SO₄)and concentrated in vacuo. Flash chromatography (2.5% MeOH/97.5% ethylacetate) provided 362 mg of hydroxy amide tetrapeptide that was oxidizedwith Dess-Martin periodinane reagent (650 mg, 1.53 mmol) and t-butanol(0.65 mL) in 5 mL of DCM at rt for 3 h. The reaction mixture wasquenched with sodium thiosulfate 1M solution (2 mL) and stirred untilthe two phases are clearly separated. The organic layer was diluted with5 more mL of DCM and washed (3×) with 10% potassium carbonate aqueoussolution (5 mL), dried (Na₂SO₄) and concentrated in vacuo. Flashchromatography (2.5% MeOH/97.5% ethyl acetate) provided 270 mg ofketoamide tetrapeptide 56. LCMS M+H=706.42, M−H=704.42. Retention Time(10-90% MeCN—H₂O with 0.1% TFA over 9 minutes)=7.73-8.81 min. LCMSM+H=682.2.

Example 23-tert-Butyl-2-(tert-butyl-dimethyl-silanyloxymethyl)-5-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (6a)

t-Butyl zinc bromide 0.5M solution in THF (3.7 mL, 1.83 mmol)was addedto a solution of enone 4a (280 mg, 0.85 mmol) in THF containing BF₃OEt₂(350 uL, 2.75 mmol) and TMSCl (465 uL) at −30° C. over a period of 5minutes. The heterogeneous mixture was stirred at −30° C. for 3.5 h thanquenched with sat'd NH₄Cl solution. Extracted with ether (3×) and thecombined extract were washed with brine, dried with sodium sulfate andconcentrated in vacuo. Flash chromatography (10% ethyl acetate-hexanes)provided 210 mg (64%) of 6a. ¹H NMR (CDCl₃) δ 3.9 (s, 1H); 3.8 (dd, 1H);3.5 (d, 1H); 2.8 (dd, 1H); 2.3 (d, 1H); 1.9 (d, 1H); 1.4 (s, 9H); 0.9(s, 18H); 0.1 (s, 3H); 0.05 (s, 3H) ppm.

Example 33-Benzyl-2-(tert-butyl-dimethyl-silanyloxymethyl)-5-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester (7a)

To a mixture of n-butyllithium (5.5 mL, 0.0086 mol) and THF at −78° C.,was added TMEDA and benzylphenylsulfide (1.91 g, 0.0095 mol). Thecolorless solution turned pale yellow. After 15 min of stirring at −78°C., the pyrolidone 4 (2.4 g, 0.0073 mol) in 10 mL of THF was addeddropwise. After the addition was completed, the reaction mixture wasstirred for 1 h at −78° C. The reaction was quenched with satd' NH₄Clsolution and the mixture warmed to rt and poured into water. Ethermixture was extracted with ethyl ether and the organic phase was washedwith brine, dried and concentrated in vacuo. Flash chromatography (20%ethyl acetate-hexane) provided 1.69 g (45%) of the desired intermediate.Reduction with 16.9 g of Ra—Ni in refluxing acetone-water (1:1) for 12 hprovided, after chromatography (2% acetone-chloroform), 1.11 g (83%) ofthe desired compound 7. ¹H NMR (CDCl₃) δ 7.3 (m, 5H); 3.8 (m, 2H); 3.7(d, 1H); 2.7-2.9 (m, 3H); 2.1 (m, 2H); 1.5 (s, 9H); 1.7 (s, 9H); 0.1 (s,6H) ppm.

Example 4 Pyrazine-2-carboxylic acid({1-[3-benzyl-2-(1-cyclopropylaminooxalyl-butylcarbamoyl)-pyrrolidine-1-carbonyl]-2,2-dimethyl-propylcarbamoyl}-cyclohexyl-methyl)-amide(65)

Prepared as described above in scheme 1 starting with intermediate 7a togive 65 with consistent analytical data. Retention Time (10-90% MeCN—H₂Owith 0.1% TFA over 6 minutes)=8.0-9.2 min. LCMS M+H=730.2

Example 5 3-Cyclohexyl-pyrrolidine-2-carboxylic acid tert-butyl ester(12a)

3-Phenyl proline 10a was hydrogenated with catalytic platinum oxide inethanol/acetic acid/water (7/2/1) under 50 psi of hydrogen for 18 h togive 3-cyclohexyl proline quantitatively. Compound 12a was preparedaccording to benzoylation and esterification from example 1; step 3.

Example 6 3-Cyclopropylmethyl-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester 2-methyl ester (A)

In a round bottom flask, a solution of the allyl proline (358 mg, 1.33mmol) in dry DCE was cooled to 0° C., and diethyl zinc in hexanes 15%(5.5 mL, 6.63 mmol) was added slowly via a syringe. To this solution wasadded chloroiodomethane (967 uL, 13.3 mmol) dropwise. The solution wasstirred at 0° C. for 20 minutes, allowed to warm to rt an stirred for 1h. The reaction mixture was cooled to 0° C. and quenched with satd'NH₄Cl solution and stirred vigorously for 10 minutes. Extracted withdichloromethane, dried with sodium sulfate and concentrated in vacuo.Chromatography (20% ethyl acetate-hexanes) gave 65 mg (17%) of thedesired product A. ¹H NMR (CDCl₃) δ 3.8 (s, 1H); 3.7 (s, 3H); 3.6-3.4(m, 2H); 2.4 (m, 1H); 2.3 (m, 1H); 1.3 (m, 3H); 0.8 (m, 1H); 0.5 (m,2H); 0.2 (m, 2H) ppm.

Example 73-Cyclopropylmethyl-1-(3-methyl-2-{3-methyl-2-[(pyrazine-2-carbonyl)-amino]-butyrylamino}-butyryl)-pyrrolidine-2-carboxylicacid methyl ester (C)

Tripeptide C was prepared by the coupling of cyclopropylmethyl proline A(41 mg, 0.16 mmol) and capped dipeptide B (52 mg, 0.16 mmol) withEDC/HOAt to give 60 mg (77%) of the desired tripeptide C afterchromatography (1:1 ethyl acetate-hexanes). ¹H NMR (CDCl₃) δ 9.4 (s,1H); 8.8 (s, 1H); 8.5 (s, 1H); 8.2 (d, 1H); 6.5 (d, 1H); 4.6 (t, 1H);4.5 (t, 1H); 4.2 (m, 1H); 3.8 (s, 3H); 3.7 (m, 2H); 2.3 (m, 4H); 2.2 (m,2H); 1.5 (s, 12H); 1.3 (m, 2H); 1.0 (m, 2H); 0.5 (m, 2H) ppm.

Example 82-(3-{[3-Cyclopropylmethyl-1-(3-methyl-2-{3-methyl-2-[(pyrazine-2-carbonyl)-amino]-butyrylamino}-butyryl)-pyrrolidine-2-carbonyl]-amino}-2-oxo-hexanoylamino)-3-phenyl-propionicacid (D)

Prepared as in example 1. Retention Time (10-90% MeCN—H₂O with 0.1% TFAover 6 minutes)=7.55-7.78 min. LCMS M+H=748.3.

Example 9 HCV Replicon Cell Assay Protocol

Cells containing hepatitis C virus (HCV) replicon were maintained inDMEM containing 10% fetal bovine serum (FBS), 0.25 mg per ml of G418,with appropriate supplements (media A).

On day 1, replicon cell monolayer was treated with a trypsin:EDTAmixture, removed, and then media A was diluted into a finalconcentration of 100,000 cells per ml with. 10,000 cells in 100 ul wereplated into each well of a 96-well tissue culture plate, and culturedovernight in a tissue culture incubator at 37° C.

On day 2, compounds (in 100% DMSO) were serially diluted into DMEMcontaining 2% FBS, 0.5% DMSO, with appropriate supplements (media B).The final concentration of DMSO was maintained at 0.5% throughout thedilution series.

Media on the replicon cell monolayer was removed, and then media Bcontaining various concentrations of compounds was added. Media Bwithout any compound was added to other wells as no compound controls.

Cells were incubated with compound or 0.5% DMSO in media B for 48 hoursin a tissue culture incubator at 37° C. At the end of the 48-hourincubation, the media was removed, and the replicon cell monolayer waswashed once with PBS and stored at −80° C. prior to RNA extraction.

Culture plates with treated replicon cell monolayers were thawed, and afixed amount of another RNA virus, such as Bovine Viral Diarrhea Virus(BVDV) was added to cells in each well. RNA extraction reagents (such asreagents from RNeasy kits) were added to the cells immediately to avoiddegradation of RNA. Total RNA was extracted according the instruction ofmanufacturer with modification to improve extraction efficiency andconsistency. Finally, total cellular RNA, including HCV replicon RNA,was eluted and stored at −80° C. until further processing.

A Taqman real-time RT-PCR quantification assay was set up with two setsof specific primers and probe. One was for HCV and the other was forBVDV. Total RNA extractants from treated HCV replicon cells was added tothe PCR reactions for quantification of both HCV and BVDV RNA in thesame PCR well. Experimental failure was flagged and rejected based onthe level of BVDV RNA in each well. The level of HCV RNA in each wellwas calculated according to a standard curve run in the same PCR plate.The percentage of inhibition or decrease of HCV RNA level due tocompound treatment was calculated using the DMSO or no compound controlas 0% of inhibition. The IC₅₀ (concentration at which 50% inhibition ofHCV RNA level is observed) was calculated from the titration curve ofany given compound.

Example 10 HCV Ki Assay Protocol

HPLC Microbore method for separation of 5AB substrate and products

Substrate: NH₂-Glu-Asp-Val-Val-(alpha)Abu-Cys-Ser-Met-Ser-Tyr-COOH

A stock solution of 20 mM 5AB (or concentration of your choice) was madein DMSO w/0.2M DTT. This was stored in aliquots at −20 C.

Buffer: 50 mM HEPES, pH 7.8; 20% glycerol; 100 mM NaCl

Total assay volume was 100 μL

X1 conc. in (μL) assay Buffer 86.5 see above 5 mM KK4A 0.5 25 μM 1 M DTT0.5 5 mM DMSO or inhibitor 2.5 2.5% v/v 50 μM tNS3 0.05 25 nM 250 μM 5AB20 25 μM (initiate)

The buffer, KK4A, DTT, and tNS3 were combined; distributed 78 μL eachinto wells of 96 well plate. This was incubated at 30 C for ˜5-10 min.

2.5 μL of appropriate concentration of test compound was dissolved inDMSO (DMSO only for control) and added to each well. This was incubatedat room temperature for 15 min.

Initiated reaction by addition of 20 μL of 250 μM 5AB substrate (25 μMconcentration is equivalent or slightly lower than the Km for 5AB).

Incubated for 20 min at 30 C.

Terminated reaction by addition of 25 μL of 10% TFA

Transferred 120 μL aliquots to HPLC vials

Separated SMSY product from substrate and KK4A by the following method:

Microbore Separation Method: Instrumentation: Agilent 1100 DegasserG1322A

Binary pump G1312A

Autosampler G1313A

Column thermostated chamber G1316ADiode array detector G1315A

Column:

Phenomenex Jupiter; 5 micron C18; 300 angstroms; 150×2 mm; P/O00F-4053-B0Column thermostat: 40 CInjection volume: 100 μLSolvent A=HPLC grade water+0.1% TFASolvent B=HPLC grade acetonitrile+0.1% TFA

Time Flow Max (min) % B (ml/min) press. 0 5 0.2 400 12 60 0.2 400 13 1000.2 400 16 100 0.2 400 17 5 0.2 400Stop time: 17 minPost-run time: 10 min.

Table 1 below depicts IC₅₀ data for certain compounds of the invention.

Compounds with Ki's ranging from 0.5 μM to >1 μM are designated A.Compounds with Ki's ranging from 0.5 μM to 0.1 μM are designated B.Compounds with Ki's below 0.1 μM are designated C. Compounds with IC₅₀'sranging from 1 μM to >10 μM are designated A. Compounds with IC₅₀'sranging from 1 μM to 0.5 μM are designated B. Compounds with IC₅₀'sbelow 0.5 μM are designated C. ND means no data.

TABLE 1 Compound Ki IC₅₀ 5 C ND 15 B ND 16 B ND 19 B ND 20 B ND 22 B ND25 B ND 26 C ND 27 C ND 28 C ND 29 C ND 30 B ND 31 C ND 32 B ND 33 B ND35 A ND 36 B ND 39 C B 41 A C 42 C ND 43 B ND 44 B B 45 A ND 46 B ND 50B ND 51 B ND 52 C C 53 B ND 54 B A 55 C B 56 B ND 57 C ND 60 ND A 62 C B63 C B 64 B A 65 C B 66 B B 67 A A 68 C C 69 C C 71 C A 72 C B 73 B A 74B A 75 B A 76 B A 77 B A

1. A compound of formula I:

or a pharmaceutically acceptable salt, or mixtures thereof, wherein: Wis:

wherein each R₆ is independently: hydrogen-, (C1-C12)-aliphatic-,(C6-C10)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-, (C3-C10)-cycloalkyl-or cycloalkenyl-, [(C3-C10)-cycloalkyl- orcycloalkenyl]-(C1-C12)-aliphatic-, (C3-C10)-heterocyclyl-,(C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, (C5-C10)-heteroaryl-, or(C5-C10)-heteroaryl-(C1-C12)-aliphatic-, or wherein up to 3 aliphaticcarbon atoms in each R₆ may be optionally replaced with S, —S(O)—,—S(O)₂—, —O—, —N—, or —N(H)— in a chemically stable arrangement; whereinR₆ may be optionally substituted with up to 3 J substituents; or two R₆groups, together with the nitrogen atom to which they are bound, mayoptionally form a 5- to 6-membered aromatic or a 3- to 7-memberedsaturated or partially unsaturated ring system wherein up to 3 ringatoms may be optionally replaced with N, NH, O, S, SO, and SO₂, whereinsaid ring system may be optionally fused to a (C6-C10)aryl,(C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl,wherein any ring has up to 3 substituents selected independently from J;wherein each R₈ is independently —OR′; or the R₈ groups together withthe boron atom, may optionally form a (C3-C10)-membered heterocyclicring wherein each R₈ is independently —OR′; or the R₈ groups togetherwith the boron atom, may optionally form a (C3-C10)-memberedheterocyclic ring having, in addition to the boron, up to 3 ring atomsoptionally replaced with N, NH, O, S, SO, and SO₂; J is halogen, —OR′,—NO₂, —CN, —CF₃, —OCF₃, —R′, oxo, thioxo, ═N(R′), ═N(OR′),1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R′)₂, —SR′, —SOR′, —SO₂R′,—SO₂N(R′)₂, —SO₃R′, —C(O)R′, —C(O)C(O)R′, —C(O)C(O)OR′, —C(O)C(O)NR′,—C(O)CH₂C(O)R′, —C(S)R′, —C(S)OR′, —C(O)OR′, —OC(O)R′, —C(O)N(R′)₂,—OC(O)N(R′)₂, —C(S)N(R′)₂, —(CH₂)₀₋₂NHC(O)R′, —N(R′)N(R′)COR′,—N(R′)N(R′)C(O)OR′, —N(R′)N(R′)CON(R′)₂, —N(R′)SO₂R′, —N(R′)SO₂N(R′)₂,—N(R′)C(O)OR′, —N(R′)C(O)R′, —N(R′)C(S)R′, —N(R′)C(O)N(R′)₂,—N(R′)C(S)N(R′)₂, —N(COR′)COR′, —N(OR′)R′, —C(═NH)N(R′)₂, —C(O)N(OR′)R′,—C(═NOR′)R′, —OP(O)(OR′)₂, —P(O)(R′)₂, —P(O)(OR′)₂, or —P(O)(H)(OR′);wherein; R′ is independently selected from: hydrogen-,(C1-C12)-aliphatic-, (C3-C10)-cycloalkyl- or -cycloalkenyl-,[(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,(C6-C10)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-,(C3-C10)-heterocyclyl-, (C3-C10)-heterocyclyl-(C1-C12)aliphatic-,(C5-C10)-heteroaryl-, and (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;wherein up to 5 atoms in R′ may be optionally and independentlysubstituted with J; wherein two R′ groups bound to the same atom mayoptionally form a 5- to 6-membered aromatic or a 3- to 7-memberedsaturated or partially unsaturated ring system wherein up to 3 ringatoms may be optionally replaced with a heteroatom independentlyselected from N, NH, O, S, SO, and SO₂, wherein said ring system may beoptionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl,(C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, wherein any ring has upto 3 substituents selected independently from J; R₅ and R_(5′) are eachindependently hydrogen or (C1-C12)-aliphatic, wherein any hydrogen maybe optionally replaced with halogen; wherein any terminal carbon atom ofR₅ may be optionally substituted with sulfhydryl or hydroxy; or R₅ is Phor —CH₂Ph and R_(5′) is H, wherein said Ph or —CH₂Ph group may beoptionally substituted with up to 3 substituents independently selectedfrom J; or R₅ and R_(5′) together with the atom to which they are boundmay optionally form a 3- to 6-membered saturated or partiallyunsaturated ring system wherein up to 2 ring atoms may be optionallyreplaced with N, NH, O, SO, or SO₂; wherein said ring system has up to 2substituents selected independently from J; R₂, R₄, and R₇ are eachindependently: hydrogen-, (C1-C12)-aliphatic-,(C3-C10)-cycloalkyl-(C1-C12)-aliphatic-, or(C6-C10)-aryl-(C1-C12)-aliphatic-; wherein up to two aliphatic carbonatoms in each of R₂, R₄, and R₇ may be optionally replaced with S,—S(O)—, —S(O)₂—, —O—, —N—, or —N(H)— in a chemically stable arrangement;wherein each of R₂, R₄, and R₇ may be independently and optionallysubstituted with up to 3 substituents independently selected from J; R₁and R₃ are each independently: (C1-C12)-aliphatic-, (C3-C10)-cycloalkyl-or -cycloalkenyl-, [(C3-C10)-cycloalkyl- or-cycloalkenyl]-(C1-C12)-aliphatic-, (C6-C10)-aryl-(C1-C12)aliphatic-, or(C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein up to 3 aliphaticcarbon atoms in each of R₁ and R₃ may be optionally replaced with S,—S(O)—, —S(O)₂—, —O—, —N—, or —N(H)— in a chemically stable arrangement;wherein each of R₁ and R₃ may be independently and optionallysubstituted with up to 3 substituents independently selected from J; R₉,R_(9′), R₁₀, and R_(10′) are each independently —X—Y-Z; X is a bond,—C(H)(R₆)—, —O—, —S—, or —N(R₁₁)—; R₁₁ is: hydrogen-,(C1-C12)-aliphatic-, (C6-C10)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-,(C3-C10)-cycloalkyl- or cycloalkenyl-, [(C3-C10)-cycloalkyl- orcycloalkenyl]-(C1-C12)-aliphatic-, (C3-C10)-heterocyclyl-,(C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, (C5-C10)-heteroaryl-, or(C5-C10)-heteroaryl-(C1-C12)-aliphatic-, wherein up to 3 aliphaticcarbon atoms in each R₁₁ may be optionally replaced with S, —S(O)—,—S(O)₂—, —O—, —N—, or —N(H)— in a chemically stable arrangement; whereinR₁₁ may be optionally substituted with up to 3 J substituents; orwherein R₁₁ and Z together with the atoms to which they are bound,optionally form a nitrogen containing 5-7-membered mono- or6-11-membered bicyclic ring system optionally substituted with up to 3 Jsubstitutents, wherein up to 3 ring atoms in said ring system may beoptionally replaced with O, NH, S, SO, or SO₂ in a chemically stablearrangement; Y is a bond, —CH₂—, —C(O)—, —C(O)C(O)—, —S(O)—, S(O)₂—, or—S(O)(NR₁₂)—; R₁₂ is: hydrogen-, (C1-C12)-aliphatic-, (C6-C10)-aryl-,(C6-C10)-aryl-(C1-C12)aliphatic-, (C3-C10)-cycloalkyl- or cycloalkenyl-,[(C3-C10)-cycloalkyl- or cycloalkenyl]-(C1-C12)-aliphatic-,(C3-C10)-heterocyclyl-, (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,(C5-C10)-heteroaryl-, or (C5-C10)-heteroaryl-(C1-C12)-aliphatic-,wherein up to 3 aliphatic carbon atoms in each R₁₂ may be optionallyreplaced with S, —S(O)—, —S(O)₂—, —O—, —N—, or —N(H)—, in a chemicallystable arrangement; wherein R₁₂ may be optionally substituted with up to3 J substituents; Z is: hydrogen-, (C1-C12)-aliphatic-,(C3-C10)-cycloalkyl- or -cycloalkenyl-, [(C3-C10)-cycloalkyl or-cycloalkenyl]-(C1-C12)-aliphatic-, (C6-C10)-aryl-,(C6-C10)-aryl-(C1-C12)aliphatic-, (C3-C10)-heterocyclyl-,(C3-C10)-heterocyclyl-(C1-C12)aliphatic-, (C5-C10)-heteroaryl-, or(C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein up to three aliphaticcarbon atoms in Z may be optionally replaced with S, —S(O)—, —S(O)₂—,—O—, —N—, or —N(H)—, in a chemically stable arrangement; wherein anyring may be optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl,(C3-C10)cycloalkyl, or (C3-C10)heterocyclyl; wherein Z may beindependently and optionally substituted with up to 3 substituentsindependently selected from J; V is —C(O)—, —S(O)—, or —S(O)₂—; R is—C(O)—, —S(O)—, —S(O)₂—, —N(R₁₂)—, —O—, or a bond; T is:(C1-C12)-aliphatic-; (C6-C10)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-,(C3-C10)-cycloalkyl or -cycloalkenyl-, [(C3-C10)-cycloalkyl or-cycloalkenyl]-(C1-C12)-aliphatic-, (C3-C10)-heterocyclyl-,(C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, (C5-C10)-heteroaryl-, or(C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein up to 3 aliphaticcarbon atoms in T may be replaced with S, —S(O)—, —S(O)₂—, —O—, —N—, or—N(H)—, in a chemically stable arrangement; wherein each T may beoptionally substituted with up to 3 J substituents; or T is selectedfrom —N(R₆)(R_(6′)); and R_(6′) is hydrogen-, (C1-C12)-aliphatic-,(C6-C10)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-, (C3-C10)-cycloalkyl-or cycloalkenyl-, [(C3-C10)-cycloalkyl- orcycloalkenyl]-(C1-C12)-aliphatic-, (C3-C10)-heterocyclyl-,(C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, (C5-C10)-heteroaryl-, or(C5-C10)-heteroaryl-(C1-C12)-aliphatic-, or wherein up to 3 aliphaticcarbon atoms in each R_(6′) may be optionally replaced with S, —S(O)—,—S(O)₂—, —O—, —N—, or —N(H)— in a chemically stable arrangement; whereinR_(6′) may be optionally substituted with up to 3 J substituents; or R₆and R_(6′), together with the nitrogen atom to which they are bound, mayoptionally form a (C3-C10)-heterocyclic ring system wherein said ringsystem may be optionally substituted with up to 3 substituentsindependently selected from J.
 2. The compound according to claim 1,wherein the

radical is,

wherein; in R′, R₁₀, and R_(10′), X and Y are both a bond and Z ishydrogen; and in R_(9′); X is a bond; Y is a bond, —CH₂—, or —C(O)—; andZ is (C1-C12)-aliphatic-, (C3-C10)-cycloalkyl- or -cycloalkenyl-,[(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,(C6-C10)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-,(C3-C10)-heterocyclyl-, (C3-C10)-heterocyclyl-(C1-C12)aliphatic-,(C5-C10)-heteroaryl-, or (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;wherein up to three aliphatic carbon atoms in Z may be optionallyreplaced with S, —S(O)—, —S(O)₂—, —O—, —N—, or —N(H)—, in a chemicallystable arrangement; wherein any ring may be optionally fused to a(C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or(C3-C10)heterocyclyl; wherein Z may be independently and optionallysubstituted with up to 3 substituents independently selected from J. 3.The compound according to claim 2, wherein in R_(9′); X is a bond; Y isa bond; and Z is (C1-C12)-aliphatic-, (C3-C10)-cycloalkyl- or-cycloalkenyl-, [(C3-C10)-cycloalkyl or-cycloalkenyl]-(C1-C12)-aliphatic-, (C6-C10)-aryl-,(C6-C10)-aryl-(C1-C12)aliphatic-, (C5-C10)-heteroaryl-, or(C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein up to three aliphaticcarbon atoms in Z may be optionally replaced with S, —S(O)—, —S(O)₂—,—O—, —N—, or —N(H)—, in a chemically stable arrangement; wherein anyring may be optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl,(C3-C10)cycloalkyl, or (C3-C10)heterocyclyl; wherein Z may beindependently and optionally substituted with up to 3 substituentsindependently selected from J.
 4. The compound according to claim 3,wherein in R_(9′); X is a bond; Y is a bond; and Z is(C1-C12)-aliphatic-, (C3-C10)-cycloalkyl- or -cycloalkenyl-,[(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-, or(C6-C10)-aryl-(C1-C12)aliphatic-, wherein up to three aliphatic carbonatoms in Z may be optionally replaced with S, —S(O)—, —S(O)₂—, —O—, —N—,or —N(H)—, in a chemically stable arrangement; wherein Z may beindependently and optionally substituted with up to 3 substituentsindependently selected from J.
 5. The compound according to claim 4,wherein R_(9′) is


6. The compound according to claim 5, wherein R_(9′) is


7. The compound according to claim 6, wherein R_(9′) is ethyl.
 8. Thecompound according to claim 1, wherein in R₉, R₁₀, and R_(10′), X and Yare both a bond and Z is hydrogen; and in R_(9′); X is a bond; Y is—C(O)—; and Z is (C1-C12)-aliphatic-, or(C3-C10)-heterocyclyl-(C1-C12)aliphatic-; wherein up to three aliphaticcarbon atoms in Z may be optionally replaced with S, —S(O)—, —S(O)₂—,—O—, —N—, or —N(H)—, in a chemically stable arrangement; wherein anyring may be optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl,(C3-C10)cycloalkyl, or (C3-C10)heterocyclyl; wherein Z may beindependently and optionally substituted with up to 3 substituentsindependently selected from J.
 9. The compound according to claim 8,wherein Z is —O—(C1-C6)-aliphatic or —N(R′)₂, wherein the two R′ groupsbound to the nitrogen atom may optionally form a 3- to 7-memberedsaturated or partially unsaturated ring system wherein up to 3 ringatoms may be optionally replaced with a heteroatom independentlyselected from N, NH, O, S, SO, and SO₂, wherein said ring system may beoptionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl,(C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, wherein any ring has upto 3 substituents selected independently from J.
 10. The compoundaccording to claim 8, wherein Z is —N(R′)₂, wherein the two R′ groupsbound to the nitrogen atom may optionally form a 3- to 7-memberedsaturated or partially unsaturated ring system wherein up to 3 ringatoms may be optionally replaced with a heteroatom independentlyselected from N, NH, O, S, SO, and SO₂, wherein said ring system may beoptionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl,(C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, wherein any ring has upto 3 substituents selected independently from J.
 11. The compoundaccording to claim 1, wherein in R′, and R₁₀, X and Y are a bond and Zis hydrogen; and in each of R₉ and R_(10′) independently; X is a bond; Yis a bond; and Z is (C1-C12)-aliphatic-, (C3-C10)-cycloalkyl- or-cycloalkenyl-, [(C3-C10)-cycloalkyl or-cycloalkenyl]-(C1-C12)-aliphatic-, (C6-C10)-aryl-,(C6-C10)-aryl-(C1-C12)aliphatic-, (C3-C10)-heterocyclyl-,(C3-C10)-heterocyclyl-(C1-C12)aliphatic-, (C5-C10)-heteroaryl-, or(C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein up to three aliphaticcarbon atoms in Z may be optionally replaced with S, —S(O)—, —S(O)₂—,—O—, —N—, or —N(H)—, in a chemically stable arrangement; wherein anyring may be optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl,(C3-C10)cycloalkyl, or (C3-C10)heterocyclyl; wherein Z may beindependently and optionally substituted with up to 3 substituentsindependently selected from J.
 12. The compound according to claim 11,wherein Z, in each of R_(9′) and R_(10′) independently, is(C1-C12)-aliphatic-, (C3-C10)-cycloalkyl- or -cycloalkenyl-, or[(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-; wherein upto three aliphatic carbon atoms in Z may be optionally replaced with S,—S(O)—, —S(O)₂—, —O—, —N—, or —N(H)—, in a chemically stablearrangement; wherein Z may be independently and optionally substitutedwith up to 3 substituents independently selected from J.
 13. Thecompound according to claim 12, wherein Z, in each of R_(9′) and R_(10′)independently, is (C1-C6)-aliphatic-.
 14. The compound according toclaim 1, wherein in R₁₀, and R_(10′), X and Y are a bond and Z ishydrogen; and in each of R₉ and R_(9′); X is a bond, Y is a bond, and Zis (C1-C6)-aliphatic-, wherein Z may be independently and optionallysubstituted with up to 3 substituents independently selected from J. 15.The compound according to claim 1, wherein W is:

wherein in the W, the NR₆R₆ is selected from —NH—(C1-C6 aliphatic), —NH—(C3-C6 cycloalkyl), —NH—CH(CH₃)-aryl, or —NH—CH(CH₃)-heteroaryl, whereinsaid aryl or said heteroaryl is optionally substituted with up to 3halogens.
 16. The compound according to claim 15, wherein in the W, theNR₆R₆ is:


17. The compound according to claim 16, wherein in the W, the NR₆R₆ is:


18. The compound according to claim 17, wherein in the W, the NR₆R₆ is:


19. The compound according to claim 18, wherein in the W, the NR₆R₆ is:


20. The compound according to claim 1, wherein R_(5′) is hydrogen and R₅is:


21. The compound according to claim 20, wherein R_(5′) is hydrogen andR₅ is:


22. The compound according to claim 1, wherein R₂, R₄, and R₇ are eachindependently H, methyl, ethyl, or propyl.
 23. The compound according toclaim 22, wherein R₂, R₄, and R₇ are each hydrogen.
 24. The compoundaccording to claim 1, wherein R₃ is:


25. The compound according to claim 24, wherein R₃ is:


26. The compound according to claim 25, wherein R₃ is:


27. The compound according to claim 1, wherein R₁ is:


28. The compound according to claim 27, wherein R₁ is:


29. The compound according to claim 18, wherein R₁ is isopropyl orcyclohexyl.
 30. The compound according to claim 1, wherein the

radical is:

wherein: R₆, R_(6′), R₇, and R₁₂, are as defined in claim
 1. 31. Thecompound according to claim 30, wherein in the

radical; R_(6′) and R₇ are both hydrogen; R₆ is: (C1-C12)-aliphatic-;(C6-C10)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-, (C3-C10)-cycloalkyl or-cycloalkenyl-, [(C3-C10)-cycloalkyl or-cycloalkenyl]-(C1-C12)-aliphatic-, (C3-C10)-heterocyclyl-,(C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, (C5-C10)-heteroaryl-, or(C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein up to 3 aliphaticcarbon atoms in R₆ may be optionally replaced by S, —S(O)—, —S(O)₂—,—O—, —N—, or —N(H)—, in a chemically stable arrangement; and wherein R₆may be optionally substituted with up to 3 substituents independentlyselected from J; and R₁₂ is as defined in claim
 1. 32. The compoundaccording to claim 31, wherein; R₆ is: (C1-C12)-aliphatic-;(C6-C10)-aryl-(C1-C12)aliphatic-, or (C3-C10)-cycloalkyl or-cycloalkenyl-; wherein up to 3 aliphatic carbon atoms in R₆ may beoptionally replaced by S, —S(O)—, —S(O)₂—, —O—, —N—, or —N(H)—, in achemically stable arrangement; wherein R₆ may be optionally substitutedwith up to 3 substituents independently selected from J; and R₁₂ is asdefined in claim
 1. 33. The compound according to claim 32, wherein theradical is:


34. The compound according to claim 33, wherein the

radical is:


35. The compound according to claim 1, wherein; V is —C(O)—; and R is abond.
 36. The compound according to claim 1, wherein; V is —C(O)—; R isa bond; and T is: (C3-C10)-heterocyclyl- or (C5-C10)heteroaryl-; whereineach T is optionally substituted with up to 3 J substituents.
 37. Thecompound according to claim 36, wherein T is (C5-C6)heterocyclyl- or(C5-C6)heteroaryl-; wherein each T is optionally substituted with up to3 J substituents.
 38. The compound according to claim 37, wherein T is:

wherein: Z′ is independently O, S, NR′, or C(R′)₂.
 39. The compoundaccording to claim 38, wherein T is:


40. The compound according to claim 1, wherein the compound is:


41. A pharmaceutical composition comprising a compound according toclaim 1 or a pharmaceutically acceptable salt or mixtures thereof in anamount effective to inhibit a serine protease; and a acceptable carrier,adjuvant or vehicle. 42.-45. (canceled)
 46. A method of inhibiting theactivity of a serine protease comprising the step of contacting saidserine protease with a compound according to claim
 1. 47. (canceled) 48.A method of treating an HCV infection in a patient comprising the stepof administering to said patient a composition according to claim 42.49.-50. (canceled)
 51. A method of eliminating or reducing HCVcontamination of a biological sample or medical or laboratory equipment,comprising the step of contacting said biological sample or medical orlaboratory equipment with a composition according to claim
 41. 52.-53.(canceled)